Abstract Significance: Wet AMD affects 1.2 M Americans and is the leading cause of blindness in those aged 55 or older. Vision improvement from anti-VEGF treatment is neither permanent nor complete, and patients must receive intravitreal injections every 1-2 months, creating a major treatment burden for patients, physicians and payers. Emerging combination therapies could address the efficacy problem, but they do not solve the treatment burden. Sustained release formulation is the most promising means to dramatically reduce injection frequency. While proven for small molecules in other indications, it has not been achieved with standard of care anti-VEGF-A drugs because, as biologics, they are much larger and more fragile, limiting molar dose and stability. Aptamers, a validated modality in AMD treatment, can be just as potent but are much smaller and more stable, and support long-term sustained release formulation. Hypothesis: We can overcome this problem with (1) next-generation aptamers that inhibit all isoforms of VEGF-A as well as SDF-1, and that are 100% modified to yield long-term in vivo stability, (2) formulation in an injectable PLGA matrix to enable 6-month sustained release. Preliminary Data: We have developed Chemically-Augmented Particle Display (CAPD), a novel platform that yields next-gen aptamers with unprecedented affinity, specificity and in vivo stability. PLGA has been FDA- approved for use in the eye, and our team has previously demonstrated its potential with aptamers. Aims: We will develop next-generation aptamers against VEGF-A and SDF-1, and compare their potency to standard of care anti-VEGF-A agents. We will formulate the aptamer in PLGA microparticles to achieve in vitro release profile lasting at least 6 months with minimal burst and high linearity. We will test PK and efficacy in a mouse laser CNV model and a rabbit NV model. We expect to demonstrate sustained in vivo efficacy for 3 months. If successful, this will establish feasibility to yield 6- month durability, and enable subsequent sustained release combination therapies to address both efficacy and treatment burden needs.